The Klotho gene is known to play a role in suppressing several different aging phenotypes, based on studies in the klotho mutant mouse. Mice homozygous for defects in the klotho gene exhibit a syndrome that closely resembles human aging, including atherosclerosis, osteoporosis, emphysema, infertility and skin atrophy. We have looked for sequence variation in the klotho gene in a paenl of well-characterized mouse strains from the Jackson Laboratory. Each exon of the klotho gene was sequenced in each of these 20 strains. No variation was found in any of the 16 laboratory derived inbred stains in the panel. However, among the 4 wild-derived inbred strains, multiple variants were found, of which five resulted in amino acid substitutions. One deletion and one insertion likely to influence the gene product were also identified. Real-time RT-PCR analysis of klotho gene expression in the wild-derived strains has shown that one of the gene variants is associated with a higher gene expression level than the others. Investigation of the clinical significance of this finding is ongoing. We have received IRB approval of a clinical protocol to look for functional variants of the Klotho gene among participants in the Batlimore Longitudinal Study on Aging. This analysis has just begun, and over the next year we will be seeking to identify specific variants of the Klotho gene associated with specific human disorders of aging, including atherosclerosis, type II diabetes, osteoporosis and osteoarthritis.